Intermittent rapamycin feeding recapitulates some effects of continuous treatment while maintaining lifespan extension

Baghdadi, Maarouf; Nespital, Tobias; Monzó, Carolina; Deelen, Joris; Grönke, Sebastian; Partridge, Linda

doi:10.1016/j.molmet.2024.101902

Cited by 2 publications

(7 citation statements)

References 82 publications

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“…2A), which improves metabolic health parameters [15] [29] and extends lifespan to a similar degree as continuous treatment [30]. As previously shown [30], intermittent rapamycin treatment extended lifespan in both sexes (p<0.0001, log rank test) with an increase in median and maximum lifespan of 17.4% and 16.5% respectively in females (Fig. 2B) and 16.6% and 18.3% respectively in males (Fig.…”

Section: Trametinib Extends Lifespan and Combines Additively With Rap...supporting

confidence: 67%

“…Indeed, trametinib plasma levels were higher in female than male mice. Rapamycin blood levels were also higher in female UM-Het3 mice [28], but there was no sex difference in rapamycin plasma levels of the intermittently fed C3B6F1 mice used in this study [30]. Noteworthy, despite the higher plasma levels, the transcriptional response towards trametinib treatment was not necessarily stronger in female than male mice, which was especially obvious in the spleen, suggesting that other processes than just drug bioavailability contribute to the sexual dimorphic molecular response.…”

Section: Discussionmentioning

confidence: 60%

“…42 mg/kg Rapamycin was chosen as the dose so far inducing the largest increase in longevity [28], and it was fed in alternate weeks (Fig. 2A), which improves metabolic health parameters [15] [29] and extends lifespan to a similar degree as continuous treatment [30]. As previously shown [30], intermittent rapamycin treatment extended lifespan in both sexes (p<0.0001, log rank test) with an increase in median and maximum lifespan of 17.4% and 16.5% respectively in females (Fig.…”

Section: Trametinib Extends Lifespan and Combines Additively With Rap...mentioning

confidence: 99%

“…The absence or presence of spleen and kidney tumours was scored with 0 or 1, respectively. Liver tumour data for rapamycin and control animals were previously published [30]. Post-mortem macropathology analysis of c-d liver and g-h spleen of animals from the lifespan and phenotyping cohort.…”

Section: Combined Drug Treatment Delays Tumour Growthmentioning

confidence: 99%

“…Numbers in brackets indicate the number of plasma samples from independent mice per treatment. Inflammation and plasma cytokine data for control and rapamycin treated animals were previously published [30].…”

Section: Combined Treatment With Trametinib and Rapamycin Reduces Inf...mentioning

confidence: 99%

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A combination of the geroprotectors trametinib and rapamycin is more effective than either drug alone

Gkioni,

Nespital,

Monzó

et al. 2024

Preprint

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Genetic suppression of activity of the insulin/IGF/mTORC1/Ras network can ameliorate the effects of ageing in animals. The network provides multiple drug targets because of its role in metabolic disease and cancer, and these are candidates for repurposing for geroprotection. For instance, inhibition of the activity of the mTORC1 complex by rapamycin can extend lifespan in multiple organisms including mice, with early indications of efficacy in humans. Trametinib inhibits MEKs in the Ras pathway and can extend lifespan in Drosophila. However, it is not yet known if trametinib alone or in combination with rapamycin can extend mouse lifespan or improve health at older ages. We assessed survival and health indices of female and male mice treated with trametinib or rapamycin alone, or with the two in combination at the same doses. Trametinib treatment extended lifespan in both sexes, while its combination with rapamycin caused further, additive prolongation. Combination treatment reduced liver tumours in both sexes and spleen tumours in males, and ameliorated the age-related increase in brain glucose uptake. There was a striking reduction in inflammation in the brain, kidney, spleen and muscle with combination treatment, accompanied by reduced circulating levels of pro-inflammatory cytokines. Trametinib alone is therefore geroprotective in mice, but combined trametinib and rapamycin treatment is more geroprotective than treatment with either drug alone, suggesting immediate translational potential for humans.

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Section: Trametinib Extends Lifespan and Combines Additively With Rap...supporting

confidence: 67%

Section: Discussionmentioning

confidence: 60%

Section: Trametinib Extends Lifespan and Combines Additively With Rap...mentioning

confidence: 99%

Section: Combined Drug Treatment Delays Tumour Growthmentioning

confidence: 99%

Section: Combined Treatment With Trametinib and Rapamycin Reduces Inf...mentioning

confidence: 99%

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A combination of the geroprotectors trametinib and rapamycin is more effective than either drug alone

Gkioni,

Nespital,

Monzó

et al. 2024

Preprint

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Functional characterisation of rare variants in genes encoding the MAPK/ERK signalling pathway identified in long-lived Leiden Longevity Study participants

Hinterding,

Baghdadi,

Gehrmann

et al. 2023

Preprint

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Human longevity, which is coupled to a compression of age-related diseases, has been shown to be heritable. However, the number of identified common genetic variants linked to this trait remains small. This may indicate that longevity is, at least to some extent, determined by rare genetic variants that are potentially even family-specific. We therefore investigated whole-genome sequencing data of long-lived families from the Leiden Longevity Study for family-specific variants. We focussed on variants residing in genes involved in the MAPK/ERK signalling pathway, a lifespan-associated pathway emerging from studies in model organisms. We then used CRISPR/Cas9 to generate transgenic mouse embryonic stem cells (mESCs) and fruit flies harbouring these variants and conducted in vitro and in vivo functional characterisation. Two variants, located in NF1 and RAF1, show opposite effects on MAPK/ERK signalling pathway activity in mESCs. At the proteomic level, we observed prominent changes that are shared between the variants (e.g. upregulation of the PI3K-AKT signalling pathway) and RAF1-specific (e.g. downregulation of oxidative phosphorylation). The variant in RAF1 also improved resistance to endoplasmic reticulum and oxidative stress in vitro. Conversely, the variant in NF1 shortened lifespan when introduced in fruit flies. In conclusion, our findings suggest that mESCs offer a good starting point for in vitro characterisation of rare genetic variants linked to human longevity. However, given the complex regulation of the MAPK/ERK signalling pathway across tissues and organisms and the large evolutionary distance between flies and humans, future studies will likely benefit from functional characterisation in human cells and model organisms evolutionary closer to humans.

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Intermittent rapamycin feeding recapitulates some effects of continuous treatment while maintaining lifespan extension

Cited by 2 publications

References 82 publications

A combination of the geroprotectors trametinib and rapamycin is more effective than either drug alone

A combination of the geroprotectors trametinib and rapamycin is more effective than either drug alone

Functional characterisation of rare variants in genes encoding the MAPK/ERK signalling pathway identified in long-lived Leiden Longevity Study participants

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